TY - JOUR
T1 - Alisertib in Combination with Weekly Paclitaxel in Patients with Advanced Breast Cancer or Recurrent Ovarian Cancer
T2 - A Randomized Clinical Trial
AU - Falchook, Gerald
AU - Coleman, Robert L.
AU - Roszak, Andrzej
AU - Behbakht, Kian
AU - Matulonis, Ursula
AU - Ray-Coquard, Isabelle
AU - Sawrycki, Piotr
AU - Duska, Linda R.
AU - Tew, William
AU - Ghamande, Sharad A
AU - Lesoin, Anne
AU - Schwartz, Peter E.
AU - Buscema, Joseph
AU - Fabbro, Michel
AU - Lortholary, Alain
AU - Goff, Barbara
AU - Kurzrock, Razelle
AU - Martin, Lainie P.
AU - Gray, Heidi J.
AU - Fu, Siqing
AU - Sheldon-Waniga, Emily
AU - Lin, Huamao Mark
AU - Venkatakrishnan, Karthik
AU - Zhou, Xiaofei
AU - Leonard, E. Jane
AU - Schilder, Russell J.
N1 - Funding Information:
Millennium Pharmaceuticals Inc, Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Part of this work was supported by the Judi Rees/Albert Pisani MD Ovarian Cancer Research Fund and the Ann Rife Cox Chair in Gynecology (Robert L. Coleman).
Funding Information:
The study was funded by Millennium Pharmaceuticals Inc, Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Part of this work was supported by the Judi Rees/Albert Pisani MD Ovarian Cancer Research Fund and the Ann Rife Cox Chair in Gynecology (Robert L. Coleman).
Funding Information:
Sheldon-Waniga, Lin, Venkatakrishnan, Zhou, and Leonard (Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited). Stock ownership: Dr Kurzrock reports ownership interest in CureMatch Inc; (Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited). Financial activity during the submitted work: Dr Falchook report grants from Millennium; Dr Coleman reports grants from Millennium; Dr Martin reports financial support to the institution for conduct of the study from Millennium Pharmaceuticals, Inc. Financial activity outside the submitted work: Dr Falchook reports grants from Millennium; Dr Coleman reports grants from Roche/ Genentech, AstraZeneca, Merck, Clovis, Esperance, Johnson & Johnson and Abbvie; Dr Ghamande reports board consulting from Advaxis Inc; Dr Goff reports grants from Millennium; Dr Kurzrock reports research funding from Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, and Guardant and consultant/advisory board fees from Actuate Therapeutics and XBiotech; Dr Martin reports financial support to the institution for conduct of the study from Novartis Pharmaceuticals Corporation, Aduro Biotech, Inc, Tetralogic Pharmaceuticals, Clovis Oncology Inc, Regeneron, Millennium Pharmaceuticals Inc, AbbVie, Amgen, and personal fees from Immunogen Inc; Dr Schilder reports personal fees from Merck, Celsion and Merck Serono. Other: Drs Falchook and Coleman report travel reimbursement to present trial results at ESGO 2013 and ESMO 2014; Dr Martin reports travel expenses for presentation of data at national meetings in November 2015 and March 2017; Intellectual property: Dr Venkatakrishnan is named inventor on published patent applications WO2103/142491 and US2013/0303519 titled “Methods of treating cancer using Aurora Kinase Inhibitors.” No other disclosures are reported. Russell J. Schilder was supported in part by NCI grant 5P30CA056036-17.
Funding Information:
Funding/Support: The study was funded by
Publisher Copyright:
© 2018 American Medical Association. All rights reserved.
PY - 2019/1
Y1 - 2019/1
N2 - Importance: There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival. Objective: This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2). Design, Setting, and Participants: An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study. Interventions: Patients were randomized 1:1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m 2 intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m 2 intravenously in 28-day cycles. Main Outcomes and Measures: Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received ≥1 dose of study drug). Results: The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75%) patients had a documented PFS event; 52 (71%) in the alisertib plus paclitaxel arm, and 55 (80%) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80% CI, 0.58-0.96; P =.14; 2-sided P value cutoff =.20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86%) vs 14 (20%) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77%) vs 7 (10%) neutropenia, 18 (25%) vs 0 stomatitis, and 10 (14%) vs 2 (3%) anemia; 54 (74%) vs 17 (25%) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug. Conclusions and Relevance: The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted. Trial Registration: ClinicalTrials.gov identifier: NCT01091428.
AB - Importance: There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival. Objective: This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2). Design, Setting, and Participants: An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study. Interventions: Patients were randomized 1:1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m 2 intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m 2 intravenously in 28-day cycles. Main Outcomes and Measures: Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received ≥1 dose of study drug). Results: The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75%) patients had a documented PFS event; 52 (71%) in the alisertib plus paclitaxel arm, and 55 (80%) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80% CI, 0.58-0.96; P =.14; 2-sided P value cutoff =.20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86%) vs 14 (20%) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77%) vs 7 (10%) neutropenia, 18 (25%) vs 0 stomatitis, and 10 (14%) vs 2 (3%) anemia; 54 (74%) vs 17 (25%) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug. Conclusions and Relevance: The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted. Trial Registration: ClinicalTrials.gov identifier: NCT01091428.
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U2 - 10.1001/jamaoncol.2018.3773
DO - 10.1001/jamaoncol.2018.3773
M3 - Article
C2 - 30347019
AN - SCOPUS:85055291610
VL - 5
JO - JAMA oncology
JF - JAMA oncology
SN - 2374-2437
IS - 1
ER -